Preoperative chemoradiation (CRT) with carboplatin (CBP)/paclitaxel (PCL) (CP) or with 5-fluorouracil (FU)/oxaliplatin (OX) (Fx) for esophageal or junctional cancer: A randomized phase 2 trial.
Authors: Antoine Adenis, Samuel Le Sourd, Xavier Mirabel, Amaury Paumier, Emilie Bogart, Veronique Vendrely, Olivier Glehen, Laetitia Dahan, Victor Simmet, Damien Bergeat, Emmanuelle Samalin, Marion Chauvenet, Xavier Benoit d'Journo, Sandrine Hiret, Caroline Gronnier, Khémara Gnep, Marie Vanseymortier, Farid El Hajbi, Marie-Cecile Le Deley, Guillaume Piessen
Journal: Journal of Clinical Oncology (2022)

4015 Background: Preoperative CRT with a FU/platinum regimen has been used for years for esophageal or junctional cancer before the CP regimen became a standard of care following the results of the CROSS study (van Hagen 2012). We aimed at evaluating the complete resection (R0) rate and severe postoperative morbidity rate associated with these 2 neoadjuvant regimens, each being combined with the radiation (RT) regime used in the CROSS trial. Methods: PROTECT is a multicenter, randomized, non-comparative, phase 2 trial (NCT02359968) in patients (pts) with resectable esophageal or Siewert type I-II junctional cancer, stage II (T1-2N1 or T3N0) or stage III (T3N1 or T4anyN) tumors (UICC-7 classification), and ECOG PS ≤2. Following randomization (balanced by ECOG PS 0 vs 1-2, stage II vs III, squamous-cell (SCC) vs adenocarcinoma (ADK), center), pts received CP (AUC2 CBP plus PCL 50mg/m² / week x 5 weeks), or Fx (FU 400 mg/m² bolus Day 1, then FU 1600 mg/m² continuous infusion over 2 days, plus OX 85 mg/m², and Folinic acid 200 mg/m², 2-h infusion, Day 1; 3 cycles every 2 weeks). RT technique was similar in both arms: 3D-conformal as published in the CROSS trial or IMRT (n = 35); total dose of 41.4Gy, 5 fractions of 1.8Gy / week, starting at Day 1 of chemotherapy. Surgery was performed 4 to 8 weeks after completion of CRT through a transthoracic or mini-invasive approach with a two field extended lymphadenectomy. Co-primary endpoints were R0 (failure: R1 or disease progression under CRT), and severe postoperative morbidity rate ≤30 days after surgery (Clavien-Dindo grade ≥ III). Based on a Bryant and Day 2-stage design (p0 = 75% and p1 = 90% for resection; p0 = 45% and p1 = 25% for morbidity; α = 10% and β = 15%), 48 evaluable pts were required by arm. Results: 100/104 pts recruited from 02/2015 to 08/2020, started the study treatment: 50 CP &amp; 50 Fx. Overall, median age = 64 (range, 33-79); 82/100 males; 62 ADK and 38 SCC; 66 esophageal and 34 junctional site; 31 stage II; 68 stage III, 1 Nx. R0 resection was obtained in 46/50 CP pts (92.0%, 95% CI: 80.8-97.8%), and in 42/48 Fx pts (87.5%, 74.8-95.3%); 2 non evaluable pts because of event unrelated to disease progression. Severe postoperative adverse events (AEs) occurred in 34/91 pts who underwent surgery: 21/48 CP (43.8%, 29.5-58.8%) and 13/43 Fx (30.2%, 17.2-46.1%). Severe AEs were respiratory disorders (CP 26%; Fx 26%), esophageal fistula (CP 18%; Fx 6%), infection (CP 5%; Fx 3%), haemorrhage (CP 5%; Fx 0%) and gastric tube necrosis (CP 6%; Fx 3%). 5 pts died from AEs (3 CP, 2 Fx). A TRG1-2 was observed in 29/48 (60.4%, 95% CI: 44.3-74.2%) CP pts, and in 19/43 (44.2%, 29.1-60.1%) Fx pts. Conclusions: When combined to preoperative radiation therapy at 41.4Gy, both regimens (CP and Fx) provided short-term benefit on R0 resection; however, CP is associated with a severe postoperative morbidity rate higher than expected. Clinical trial information: NCT02359968.